Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

Abstract

The mesodermally derived normal ovarian surface epithelium (OSE) displays both epithelial and mesenchymal characteristics and exhibits remarkable phenotypic plasticity during post-ovulatory repair. The majority of epithelial ovarian carcinomas (EOC) are derived from the OSE and represent the most lethal of all gynecological malignancies, as most patients (~70%) present at diagnosis with disseminated intra-abdominal metastasis. The predominant pattern of EOC metastasis involves pelvic dissemination rather than lymphatic or hematologic spread, distinguishing EOC from other solid tumors. Acquisition of the metastatic phenotype involves a complex series of interrelated cellular events leading to dissociation (shedding) and dispersal of malignant cells. A key event in this process is disruption of cell-cell contacts via modulation of intercellular junctional components. In contrast to most carcinomas that downregulate E-cadherin expression during tumor progression, an unique feature of primary well-differentiated ovarian cancers is a gain of epithelial features, characterized by an increase in expression of E-cadherin. Subsequent reacquisition of mesenchymal features is observed in more advanced tumors with concomitant loss of E-cadherin expression and/ or function during progression to metastasis. The functional consequences of this remarkable phenotypic plasticity are not fully understood, but may play a role in modulation of cell survival in suspension (ascites), chemoresistance, and intraperitoneal anchoring of metastatic lesions. Keywords ovarian cancer; epithelium; cadherin; keratin; vimentin; epithelial-mesenchymal transition; plasticity Ovarian Cancer-OverviewTumors arising from the ovarian epithelium account for ~90% of ovarian malignancies and epithelial ovarian carcinoma (EOC) is the leading cause of death from gynecologic malignancy, resulting in approximately 15,280 deaths in the United States alone in 2006 [1]. These distressing statistics are largely due to the low detection rate of disease confined to the ovary (stage 1) when 5-year survival is >90%. Approximately 75% of women are initially diagnosed with disseminated intra-abdominal disease (stage III-IV) and have a 5-year survival of <20%.Ovarian tumors are pathologically heterogeneous with four major histotypes: serous, endometroid, clear cell and mucinous. These classifications are histogenetically based on The early steps of EOC metastasis involve shedding of the cells from the primary tumor to form free floating cells or multi-cellular aggregates (MCAs) in ascites [ Fig. 1]. Cell-cell and cell-matrix adhesion molecules mediate interaction of metastasizing tumor cells with mesothelial cells lining the inner surface of the peritoneal cavity and the sub-mesothelial extracellular matrix (ECM). Localized proteolytic degradation of sub-mesothelial ECM components facilitates migration of tumor cells and anchoring of secondary lesions on adjacent pelvic organs, and at later stages, metastasis to distant organs [9,10]. However, the majority of wo...

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

“…Modulation of cell-cell and cell-matrix adhesion are key events in ovarian cancer metastasis, as intraperitoneal adhesion of malignant cells and multicellular aggregates combined with localized integrin-mediated invasion of the collagen-rich submesothelial matrix are necessary to anchor secondary lesions (5,40). Intraperitoneal ovarian cancer metastasis is mediated by adhesion via integrins ␣2␤1 and ␣3␤1 to peritoneal mesothelial cells displaying surface expression of collagen and the exposed interstitial (types I and III) collagen-rich submesothelial matrix, and antibodies directed against these integrins block collagen binding (41)(42)(43)(44)(45)(46)(47).…”

“…In addition to enzymes and enzyme receptors, expression of two genes commonly associated with EMT, vimentin and snail, was also induced by integrin clustering. Ovarian cancers typically display both epithelial and mesenchymal characteristics, and the mesenchymal marker vimentin is widely expressed in tumor specimens (5). Snail is a key inducer of EMT and functions as a negative regulator of E-cadherin transcription.…”

“…However, a unique feature of EOC is that E-cadherin becomes more abundant in primary differentiated carcinomas, with all histotypes displaying strong immunoreactivity (reviewed in Refs. 5,6). There is less clarity regarding relative E-cadherin levels during ovarian tumor progression and metastasis.…”

Evolution of adaptive phenotypic traits without positive Darwinian selection

“…(2) Tumor cells show evidence of phenotypic plasticity that is adaptive from the point of view of the tumor, in terms of processes such as tumor growth, survival and metastasis (Yacoby, 2005;Hudson et al, 2008). The molecular basis of tumor plasticity remains poorly understood, although presumably it makes use of mechanisms that have a role in normal development (Feinberg, 2007).…”

3-Deazaneplanocin A is a Promising Therapeutic Agent for Ovarian Cancer Cells

“…E-cadherin is a cell adhesion protein, which plays a major role in maintaining intercellular junction in epithelial tissue (Davies et al, 1998;Landen et al, 2008). E-cadherin is uniformly expressed in ovarian inclusion cysts, benign ovarian cancers and ovarian cancer (Imai et al, 2004;Hudson et al, 2008). We found that E-cadherin was significantly upregulated after treatment with 5μM DZNep for 48 h.…”